Timing and localization of human dystrophin isoform expression provide insights into the cognitive phenotype of Duchenne muscular dystrophy

Nathalie Doorenweerd,Ahmed Mahfouz,Annemieke M Aartsma-Rus,Erik H Niks,Jan J G M Verschuuren,Rajaram Kaliyaperumal,Peter A C T’ Hoen,Hermien E Kan,Maaike Van Putten,Marcel J T Reinders,Jos G M Hendriksen,Boudewijn P F Lelieveldt

doi:10.1038/s41598-017-12981-5

Abstract

Duchenne muscular dystrophy (DMD) is a muscular dystrophy with high incidence of learning and behavioural problems and is associated with neurodevelopmental disorders. To gain more insights into the role of dystrophin in this cognitive phenotype, we performed a comprehensive analysis of the expression patterns of dystrophin isoforms across human brain development, using unique transcriptomic data from Allen Human Brain and BrainSpan atlases. Dystrophin isoforms show large changes in expression through life with pronounced differences between the foetal and adult human brain. The Dp140 isoform was expressed in the cerebral cortex only in foetal life stages, while in the cerebellum it was also expressed postnatally. The Purkinje isoform Dp427p was virtually absent. The expression of dystrophin isoforms was significantly associated with genes implicated in neurodevelopmental disorders, like autism spectrum disorders or attention-deficit hyper-activity disorders, which are known to be associated to DMD. We also identified relevant functional associations of the different isoforms, like an association with axon guidance or neuron differentiation during early development. Our results point to the crucial role of several dystrophin isoforms in the development and function of the human brain.

Highlights

Duchenne muscular dystrophy (DMD) is a muscular dystrophy with high incidence of learning and behavioural problems and is associated with neurodevelopmental disorders
In order to assess the expression of the different dystrophin isoforms, we used the expression of the unique first exons of Dp427p, Dp427c, Dp427m, Dp260, Dp140, Dp116 and the shared first exon of Dp71 and Dp40 (Fig. 2)
We provide a comprehensive study of the expression of dystrophin isoforms in healthy human brain across anatomical regions and developmental stages

Summary

Introduction

Duchenne muscular dystrophy (DMD) is a muscular dystrophy with high incidence of learning and behavioural problems and is associated with neurodevelopmental disorders. The expression of dystrophin isoforms was significantly associated with genes implicated in neurodevelopmental disorders, like autism spectrum disorders or attention-deficit hyper-activity disorders, which are known to be associated to DMD. Our results point to the crucial role of several dystrophin isoforms in the development and function of the human brain. The localization and function of the full-length muscle isoform Dp427m is well characterized both in humans and animal models. It is a crucial component of the dystrophin-glycoprotein complex (DGC), which bridges the inner cytoskeleton and the extracellular matrix providing structural stability to muscle fibers[12,13]. The Dp71 isoform is ubiquitously expressed, with higher levels in the central nervous system (CNS)[22,23]

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Results

Conclusion